Process for diagnosing hypercyanogenesis

ABSTRACT

Hypercyanogenesis is diagnosed by injecting a human patient parenterally with hydroxocobalamine to produce cyanocobalamine, collecting the urine of the patient, decomposing the cyanocobalamine eliminated with the urine by photolysis, and determining the quantity of the thus-liberated hydrocyanic acid. The cyanide level following injection will vary, always initially increasing. In a normal patient, the cyanide level will rapidly thereafter fall to that of hypocyanosis; but in a patient afflicted with persistent hypercyanogenesis, the cyanide level will fall only relatively slowly toward its initial value.

[4 1 Sept. 2, 1975 PROCESS FOR DIAGNOSING HYPERCYANOGENESIS [75] Inventor: Michel Rolland, Paris, France [73] Assignee: Societe Anonyme: Albert Rolland S.A., Paris. France [22] Filed: Sept. 15, 1972 [21] Appl. No.: 289,291

[30] Foreign Application Priority Data Sept. 21, 1971 France 71.33923 [52] US. Cl. 424/9; 424/129; 424/201 [51] Int. Cl. A61K 29/00; A61K 31/68;

G01N 31/00; GOIN 33/16 [58] Field of Search 424/9, 129, 20K

[56] I References Cited I OTHER PUBLICATIONS Mushett, PSEBM, Vol.81, 1952, pp. 234-237.

Glass, Nature, Vol. 189, Jan. 14, 1961, pp. 138-140.

Primary E.\'uminerAlbert T. Meyers Assistant E.\-mninerA. P. Fagelson Attorney, Agent, or Firm-Y0ung & Thompson [57] ABSTRACT Hypercyanogenesis is diagnosed by injecting a human patient parenterally with hydroxocobalamine to produce cyanocobalamine, collecting the urine of the patient, decomposing the cyanocobalamine eliminated with the urine by photolysis, and determining the quantity of the thus-liberated hydrocyanic acid. The cyanide level following injection will vary, always initially increasing. In a normal patient, the cyanide level will rapidly thereafter fall to that of hypocyanosis; but in a patient afflicted with persistent hypercyanogene sis, the cyanide level will fall only relatively slowly toward its initial value.

1 Claim, No Drawings PROCESS FOR'DIAGNOSING HYPERCYQNOGENES'IS It has been established, by clinical observations, that certainillnesses, such as disseminated sclerosis'and certain algias, were at least partially.e-ausedbyghypercyanosis. It has already been proposed ,to use hydroxocobalamine for counteracting. acute cyanide poisoning caused by hydrocyanic acid, and for the. treatment of various otherillnesses, Ho wcver it has never been proposed to use ,hydroxocobalamineffor diagnosing chronic hypercyanogenesis which; set 'forthfabove, may be at least the partial cause'iof certain' illnesses.

In normalhcalthja huinan beingeliminates cyanide ions in the urine a rate of approximately gamma every 24 hours. When the quantity eliminated exceeds this figure, the cyanide ion content of the bloodis too high, but it is important to be able todiagnose whether hypercyanogenesis is the cause of such illness.

The object of the present invention is to provide a process for diagnosing hypercyanogenesis by provoking hypercyanogcnesis, that is to say, by provoking an accelerated elimination of the cyanide ions present in excess of normal in the blood. 7

The present invention is based on the analysis of the action of hy droxocobalamine on hydrocyanic acid and cyanide compounds in general and of clinical observations which have confirmed the possibility of using hydroxocobalamine as 'a diagnostic agent for hypercyanogenesis, this diagnostic agent simultaneously also having a curative action.

When hydroxoeobalamine is in the presence of hydrocyanic acid or an aqueous solution of cyanide, one molecule of hydroxocobalamine combines with one I molecule of hydrocyanic acid or cyanide with the fortnation of one molecule of cyanocobalamine. Since cyanocobalamine is not toxic, it has been proposed to use eliminated in the urine.

The present invention therefore provides a process :for diagnosing hypercyanogenesis characterized in that a a patient is injected parenterally with a high dose of hydroxocobalamine, the urine is collected, the cyanocobalamine expelled with the urine is decomposed by I photolysis, and the thus-liberated hydrocyanic acid is quantitatively determined.

1-; When the process was carried out, it was seen that, I in the absence of any cause capable of producing a cya- 1 nuria of exogenous origin, the administration of hy- T ldroxocobalamine is followed by urinary hypercyanosis and this hypercyanuria may vary with the condition of the subject and is characteristic of a hypercyanogenesis appearing simultaneously with algias.

The dosage units of the present invention are preferably contained in injectable ampoules each containing a dose of mg. of hydroxocobalamine.

. i The following clinical observations are given by way On the first subject, the quantitative analysis was effected of the ions CN in gammas in the urine per 24 droxocobalamine, thi'slfigure increased to l .3 At the end of 48 hours ithad dropped back to 0.95 and a further injection was effected of 5 ,000y of .hydroxocobalamine; which caused therz-itc to clirnb'ba'ck. 72 hours after the firstinjection. to '1 fl y..After 96 hours. ie, 48 hours after the second injection, the rate had dropped was administered by intramuscular means. The quantitative analysis of the CN ions in gammas per 24 hours was, 24 hours after injection, 8.9, 48 hours after injection. 0.7, and 72 hours after the said injection 09.

The subject was therefore afflictcd with endogenous hydrocyanic auto-intoxication, the normal level of the urinary hydrocyanic acid being reestablished by a single injection of hydroxocobalamine.

OBSERVATION NO. 3

In a subject it was discovered. before any treatment. that 1.75-y of CN' ions per 24 hours was present in the urine. The subject was subjected to several successive injections of hydroxocobalamine, namely, an initial injection of 10,000 followed 24 hours later with an injection of 20,0007, then an injection of 30.00031 24 hours later, then an injection of 20,000 every 24 hours.

The results of the analyses .were as follows:

Time Injection CN" in 'y per 24 hours 0 l0,000 7 L75 24h 20,000 y lib 48h 30,000 -y 2.3 72h 20,000 'y 20.6 96th 20,000 7 8.4 l20h 3.0

It will be seen that the subject is afflicted with a persistent hypercyanogenesis, the administration of a new dose of hydroxocobalamine or a stronger dose causing a hypercyanuria which is even higher, without return to the normal cyanuria.

It will be seen that the diagnosis has made it possible to confirm on patients having, before any treatment, a hypercyanogencsis, the existence of a syndrome of an endogenous cyanideauto-intoxication. The biochemical sign represented by a high content of cyanide ions before any treatment is confirmed and is much more easily detectable since it is greater with the process according to the invention. I

Prolonged observations on subjects afflicted with evolutive bouts of disseminated sclerosis have made it possible to confirm a very clearhypercyanuria, sometimes very high, since it may reach 807 and more of uri- 3 nary hydrocyanic acid in-theeourse ofv the evolutive bouts the injection of the diagnostic agent'simultaneously producing an absence or attenuation of the pain whichhad not been noticed during previ ous bouts From a consideration; of the. .foregoing disclosure, therefore, it will be evident that theinitially recited ob: ject of the present invention has been achieved Although the present invention has been described and illustrated in connection with preferred emoojdb ments, it is to be understood thati modi ficatioris and variations maybe resortcd toj without departing from the spirit of the invention, asthose slgill'ed int his art will readily understand. Such modifications and variations are considered to be within the purview and scope of the present invention as defined by the appended claims. :2, 1"

Having described my in vention. l claim l. A process for diagnosing hyper cyanogenesis, corn- H 4 prising the steps ;of injecting a human patient parenterally with hydroxoeobalamine, collecting the urine of the patient, decomposing the cyanocobalamine eliminatedwit-h. the: urine by photolysis, determining the quantity of the thus-liberated 'hydrocyanic acid, repeating said injecting and collecting and decomposing and any saidinjecting step in respect of the same human patient, and comparing the thus-determined quantities of hydrocyanic"acid with the quantities of hydrocyanic acid Characteristic of a normal human patient at the same said intervals of time, thereby to detect the pres.- ence of hypereyanogenesis. I 

1. A PROCESS FOR DIAGNOSING HYPERCYANOGENESIS, COMPRISING THE STEPS OF INJECTING A HUMAN PATIENT PARENTERALLY WITH HYDROXOCOBALAMINE, COLLECTING THE URINE OF THE PATIENT, DECOMPOSING THE CYANOCOBALMINE ELIMINATED WITH THE URINE BY PHOTOLYSIS, DETERMINING THE QUALITY OF THE THUS-LIBIRATED HYDROCYANIC ACID, REPEATING SAID COLLECTING AND DECOMPOSING AND DETERMINING STEPS AT A PLURALITY OF PREDETERMINED EQUAL INTERVALS OF TIME AFTER THE FIRST SAID INJECTING STEP IN RESPECT OF THE SAME HUMAN PATIENT, ALSO PERFORMING SAID COLLECTING, DECOMPOSING AND DETERMINING STEPS PRIOR TO ANY SAID INJECTING STEP IN RESPECT OF THE SAME HUMAN PATIENT, AND COMPARING THE THUS DETERMINED QUANTITIES OF HYDROCYANIC ACID WITH THE QUANTITIES OF HYDROCYANIC ACID CHARACTERISTIC OF AN NORMAL HUMAN PATIENT AT THE SAME SAID INTERVALS OF TIME, THEREBY TO DETECT THE PRESENCE OF HYPERCYANOGENESIS. 